Total Synthesis of Lamellarin D Trimethyl Ether, Lamellarin D, and Lamellarin H

Article abstract of DOI:10.1021/acs.joc.7b00636

Total syntheses of three different lamellarins have been accomplished using a Ru(II)-catalyzed (3 + 2) annulation strategy to construct the central pyrrole ring. The striking features of this synthesis are the use of PEG-400 as a green solvent for the (3

Full text of DOI:10.1021/acs.joc.7b00636

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Note
Total Synthesis of Lamellarin D Trimethyl Ether, Lamellarin D and Lamellarin H
Dhanaji M Lade, Amit B. Pawar, Prathama S. Mainkar, and Srivari Chandrasekhar
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 19 Apr 2017
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Total Synthesis of Lamellarin D Trimethyl Ether, Lamellarin D and
Lamellarin H
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Dhanaji M. Lade†,‡, Amit B. Pawar†, Prathama S. Mainkar† and Srivari Chandrasekhar*†,‡
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†Division of Natural Products Chemistry, CSIRꢀIndian Institute of Chemical Technology, Hyderabad 500007, India
‡Academy of Scientific and Innovative Research (AcSIR), New Delhi, India
Email: srivaric@iict.res.in
ABSTRACT: Total syntheses of three different lamellarins have been accomplished using Ru(II)ꢀ
catalyzed (3+2) annulation strategy to construct central pyrrole ring. The striking features of this
synthesis are use of PEGꢀ400 as a green solvent for (3+2) annulation reaction and multiple catalytic
reactions with excellent over all yield. The present route also enables the synthesis of various
lamellarin analogues devoid of B ring.
The central pyrrole ring containing natural products are abundant in nature.1 Lamellarins represent a
large part of this class having marine origin. Faulkner et al. were the first to isolate lamellarins in
1985 from prosobranch mollusc Lamellaria sp.2 Many lamellarins show profound biological effects
including cytotoxicity against various cancers, inhibition of HIVꢀI integrase etc.3 So far, more than 50
lamellarins have been isolated and well characterized. The most bioactive lamellarins include D, G, H,
L and N (Figure 1). Of these, lamellarin D was shown to be a promising topoisomerase I inhibitor and
was also found to be responsible for triggering mitochondrial permeability transition.4 Owing to their
interesting structural features and biological activities, many synthetic chemistry groups embarked on
developing efficient syntheses of lamellarins. The reviews by Opatz, Alvarez and Handy; on all the
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synthetic approaches reported till 2014 highlight the major developments in total synthesis of
lamellarins.5
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Figure 1. Biologically Active Lamellarins
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A few more total syntheses were reported in the last couple of years engaging efficient and modular
strategies.6 The interesting biological properties exhibited by lamellarins, especially against HIV and
Malaria, prompted us to explore a scalable and flexible synthesis of lamellarin D trimethyl ether,
lamellarin H and lamellarin D which also could be extended to other lamellarin class of natural
products and analogues with minimal synthetic operations.
Scheme 1. Synthesis of Functionalized Pyrroles for Lamellarin Synthesis
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A major challenge in the synthesis of lamellarins is to synthesize the central functionalized pyrrole
ring. This can be achieved via two different methods; first is the functionalization of simple pyrrole
moiety and other is to synthesize functionalized pyrrole in one step from appropriate acyclic
precursors (Scheme 1). For instance, Iwao et. al has synthesized functionalized pyrrole 7 starting from
pyrrole in 6 steps in their synthesis of lamellarin L and N.6a On the other hand, Opatz and coꢀworkers
prepared iodoꢀpyrrole derivative 8 in 3 steps for the synthesis of lamellarin D trimethyl ether and
lamellarin H starting from veratraldehyde.6b Handy et al. started their synthesis of lamellarin G
trimethyl ether from pyrrole wherein the functionalized pyrrole 9 was synthesized in 6 steps.7 Alvarez
group has synthesized bromoꢀpyrrole derivative 10 for the synthesis of lamellarin D starting from
methyl pyrroleꢀ2ꢀcarboxylate in 4 steps.8 Banwell and coꢀworkers reported the synthesis of lamellarin
G trimethyl ether from NꢀBoc pyrrole wherein; they have synthesized bromoꢀpyrrole precursor 11 in 5
steps.9 Gupton et al. described formal total synthesis of lamellarin G trimethyl ether starting from
substituted phenylacetic acid derivative to prepare intermediate 12 in 4 steps.10 Jia et al. has
synthesized triꢀarylated pyrrole derivative 13 in 4 steps starting from vanillin in their synthesis of
lamellarin D and H.11 Steglich group has reported synthesis of fully functionalized pyrrole 14 in 5
steps for the synthesis of lamellarin L using Oꢀisopropylisovanillin as a starting material.12 More
recently, Yamaguchi and Itami et al. reported synthesis lamellarin L and C starting from 2,3,4ꢀ
trimethoxybenzaldehyde in which a key pyrrole intermediate 15 was synthesized in 4 steps.6c The
major limitation of these approaches is the multistep synthesis of functionalized pyrrole required for
the synthesis of lamellarins. We desired to develop a more flexible strategy which can provide
advanced intermediate in a more concise manner with high yield to access diverse lamellarins along
with their analogues.
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In recent times, transition metal catalyzed C−H functionalization has emerged as a successful tool in
the area of total synthesis of natural products.13,14 To the best of our knowledge, C−H
functionalization strategy has never been utilized in the synthesis of lamellarins. In 2011, Ackermann
and Wang group independently reported an elegant Ru(II)ꢀcatalyzed (3+2) annulation of enamides
and alkynes for the synthesis of pyrroles.15,16 However, utilization of this reaction for the total
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synthesis of natural products is still unrevealed. Herein, we report the total synthesis of lamerllarin D
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trimethyl ether, D and H using Ruꢀcatalyzed C−H functionalization strategy.
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According to the retrosynthetic analysis (Scheme 2) lamellarins can be obtained from the coupling of
bromopyrrole derivative 19 with appropriate boronic acid 18 followed by lactonization and
PomeranzꢀFritsch type cyclization. The bromopyrrole 19 can be synthesized from key intermediate 17
which in turn could be constructed via Ruꢀcatalyzed (3+2) oxidative annulation of enamide 16a and
diarylalkyne 20. The diarylalkyne 20 can be easily synthesized from aryl bromide 21 and
commercially available propiolic acid using Pdꢀcatalyzed decarboxylative crossꢀcoupling.17
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Scheme 2. Retrosynthetic Analysis
Our synthetic sequence (Scheme 3) commenced with the annulation reaction between enamide 16a
and diarylalkyne 20a in presence of 5 mol % of [Ru(pꢀcymene)Cl2]2 as catalyst and Cu(OAc)2.H2O as
oxidant in PEGꢀ400 to furnish 2,3ꢀdiaryl pyrroleꢀ5ꢀcarboxylate 17a in 90% yield. Recently, PEG has
been used as a solvent for various Ru(II)ꢀcatalyzed C−H activation.18 Bromination of 17a with NBS in
DMF yielded bromoꢀpyrrole 19a in 82% yield. The Suzuki reaction between boronic acid 18a and
bromide 19a with Pd(dba)2 in presence of 1,1'ꢀbis(diphenylphosphino) ferrocene (dppf) furnished the
tetrasubstituted pyrrole 22a in 85% yield. The one pot two step lactonization by MOM deprotection
catalyzed by TsOH in MeOH furnished lactone 23a in 95% yield. The Nꢀalkylation of 23a with
bromoacetaldehyde diethyl acetal furnished 24a; which upon Iwao’s intramolecular6a TfOHꢀmediated
cyclization strategy generated lamellarin D trimethyl ether (2) in 94% yield. The global deprotection
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of methyl ethers with BBr3 yielded lamellarin H (3) in 83% yield. The overall yields for lamellarin D
trimethyl ether (2) and lamellarin H (3) were 44% and 37% respectively.
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Scheme 3. Modular Total Synthesis of Lamellarin D Trimethyl Ether, Lamellarin D and
Lamellarin H
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After successfully synthesizing lamellarin D trimethyl ether and lamellarin H, we turned our attention
towards synthesis of lamellarin D (1). The synthesis of lamellarin D began with Ru(II)ꢀcatalyzed
(3+2) annulation of enamide 16a with diarylalkynes 20b to furnish pyrrole 17b. Later on, similar
synthetic sequence (bromination, Suzuki reaction, Nꢀalkylation and cyclization) was followed, as
described for lamellarin H synthesis, to furnish intermediate 25. The intermediate 25 on treatment
with BCl3 furnished lamellarin D in 79% yield with 29% overall yield.
Scheme 4. Synthesis of Lamellarin Analogues
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Finally, this modular synthetic strategy was applied for the synthesis of various lamellarin analogues.
For this purpose, different diarylalkynes have been used in the Ruꢀcatalyzed annulation reaction of
enamide to furnished differently substituted pyrroles. Later on, similar synthetic operations were
carried to furnish lactones (23c−23e) as described in Scheme 4. These lactones structurally resembles
lamellarins devoid of B ring.
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In conclusion, we have developed modular synthetic approach for the synthesis of various lamellarins
and their analogues in an efficient and concise manner. The key steps involve Ruꢀcatalyzed (3+2)
annulation in PEG, Suzuki reaction and TfOH catalyzed cyclization. This work is amenable for
synthesis of other natural products which have substituted pyrrole as the core.
EXPERIMENTAL SECTION
General Remarks
Unless otherwise stated, all commercial reagents and solvents were used without additional
purification. Analytical thin layer chromatography (TLC) was performed on preꢀcoated silica gel 60
F254 plates. Visualization on TLC was achieved by the use of UV light (254 nm). Column
chromatography was undertaken on silica gel (100‒200 mesh) using a proper eluent system. NMR
spectra were recorded in chloroformꢀd and DMSOꢀd6 at 300 or 400 or 500 MHz for 1H NMR spectra
and 75 MHz or 100 or 125 MHz for 13C NMR spectra. Chemical shifts were quoted in parts per
million (ppm) referenced to the appropriate solvent peak or 0.0 ppm for tetramethylsilane. The
following abbreviations were used to describe peak splitting patterns when appropriate: br = broad, s
= singlet, d = doublet, t = triplet, q = quartet, sept = septet, dd = doublet of doublet, td = triplet of
doublet, m = multiplet. Coupling constants, J, were reported in Hertz unit (Hz). For 13C NMR
chemical shifts were reported in ppm referenced to the center of a triplet at 77.0 ppm of chloroformꢀd
and 40.0 ppm center for DMSOꢀd6. HRMS spectra were recorded using ESIꢀTOF techniques.
[RuCl2(pꢀcymene)]2was purchased from sigma aldrich.
1,2ꢀbis(3,4ꢀDimethoxyphenyl)ethyne (20a).19 The diarylalkyne was prepared by using Lee et al.
protocol16 by modifying reaction condition: In a round bottam flask under nitrogen atmosphere were
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placed propiolic acid (700 mg, 1.0 mol, 1 equiv), bromoveratrol 21a (434 mg, 2.0 mol, 2 equiv),
PdCl2(PPh3)2 (171 mg, 5 mol%, 0.05 equiv), dppb (426 mg, 10 mol %, 0.1 equiv), DBU (3.05 gm, 2.0
mol, 2 equiv) and DMSO (30 mL).The resulting reaction mixture was heated at 110 ⁰C for 24 h, after
completion of the reaction it was diluted with saturated NH4Cl solution (250 mL) and extracted with
ethyl acetate (50 mL × 3), washed with brine, dried on Na2SO4. The solvent was removed under
vacuo, crude mixture was purified by column chromatography on silica gel to furnish 20a as white
solid (2.4 gm, 80%). mp 155–156 °C; 1H NMR (400 MHz, CDCl3) δ 7.13 (dd, J = 8.3, 1.9 Hz, 2H),
7.04 (d, J = 1.8 Hz, 2H), 6.83 (d, J = 8.3 Hz, 2H), 3.90 (s, 6H), 3.89 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 149.2, 148.6, 124.6, 115.6, 114.1, 111.0, 87.9, 55.8.
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Ethyl 4,5ꢀbis(3,4ꢀdimethoxyphenyl)ꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate (17a). In a sealed tube a mixture of
ethyl 2ꢀacedamidoacrylate 16a (471 mg, 3.00 mmol), 1,2ꢀbis(3,4ꢀdimethoxyphenyl)ethyne 20a (982
mg, 3.30 mmol), [RuCl2(pꢀcymene)]2 (91.0 mg, 5.0 mol %) and Cu(OAc)2·H2O (598 mg, 3.00 mmol)
in PEGꢀ400 (5 mL) was stirred at 100 °C for 24 h. After completion ot the reaction (TLC), the
reaction mixture was cooled to room temperature, then reaction mixture was diluted with sat. aq.NH3
(30%, 50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic phase was washed with
brine and dried over anhydrous Na2SO4. After filtration and evaporation of the solvents under reduced
pressure, the crude product was purified by column chromatography on silica gel (nꢀhexane/EtOAc :
2:1) to yield 17a as white solid (940 mg, 90%). mp 127–129 °C; IR (neat) ν (cm−1) = 3306, 2939,
2836, 1678, 1566, 1521, 1470, 1314, 1243, 1213, 1134, 1026, 811, 759; 1H NMR (300 MHz, CDCl3)
δ 9.30 (s, 1H), 7.04 (d, J = 2.4 Hz, 1H), 6.98 (dd, J = 8.3, 1.6 Hz, 1H), 6.92–6.78 (m, 5H), 4.32 (q, J =
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7.1 Hz, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 3.73 (s, 3H), 3.70 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H); C NMR
(75 MHz, CDCl3) δ 161.3, 148.9, 148.8,148.6, 147.6, 132.8, 128.2, 124.6, 123.3, 121.8, 120.7, 120.2,
116.3, 111.9, 111.3, 111.23,111.20, 60.4, 55.9, 55.8, 55.7, 14.5; HRMS (ESI) m/z calcd. for
C23H25NNaO6[M+Na]+: 434.1580, found: 434.1559.
Ethyl 3ꢀbromoꢀ4,5ꢀbis(3,4ꢀdimethoxyphenyl)ꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate (19a). Under nitrogen
atmosphere, NBS (178 mg, 1 mmol) was added portionwise to a solution of 17a (411 mg, 1 mmol) in
DMF (20 mL) at 0 °C. After stirring reaction mixture at 0 °C for 1 h, then it was warmed to room
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temperature and stir for another 12 h. Then it was diluted with water and extracted with EtOAc (2 ×
50 mL). The combined organic layer was washed with brine, dried over Na2SO4, and evaporated. The
residue was purified by column chromatography over silica gel (hexane/ethyl acetate = 2:1) to give
19a as a colourless solid (405 mg, 82%); mp 174–176 °C; IR (neat) ν (cm−1) = 3289, 2937, 2837,
1669, 1521, 1472, 1246, 1141, 1029, 758; 1H NMR (400 MHz, CDCl3) δ 9.41 (s, 1H), 6.90–6.86 (m,
2H), 6.86–6.82 (m, 2H), 6.80 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 2.0 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H),
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3.90 (s, 3H), 3.86 (s, 3H), 3.78 (s, 3H), 3.61 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H); C NMR (100 MHz,
CDCl3) δ 160.5, 149.0, 148.7, 148.6, 148.2, 133.1, 126.1, 124.3, 123.6, 123.2, 119.6, 119.3, 114.0,
111.1, 111.0, 110.8, 106.0, 60.9, 55.84, 55.81, 55.6, 14.4; HRMS (ESI) m/z calcd. for C23H24
BrNNaO6 [M+Na]+: 512.0679, found: 512.0705.
Ethyl
3ꢀ(4,5ꢀdimethoxyꢀ2ꢀ(methoxymethoxy)phenyl)ꢀ4,5ꢀbis(3,4ꢀdimethoxyphenyl)ꢀ1Hꢀpyrroleꢀ2ꢀ
carboxylate (22a). Under nitrogen atmosphere, a mixture of 19a (98 mg, 0.2 mmol), 18a (72 mg, 0.3
mmol), Pd(dba)2 (11.5 mg, 10 mol %), dppf (11.1 mg, 10 mol %), Na2CO3 (140 mg, 1.26 mmol),
DME (5.0 mL), and degassed water (1.0 mL) was refluxed for 18 h. After cooling to room
temperature, the solvent was evaporated, and the crude residue was extracted with DCM. The extract
was washed with water and brine, dried over Na2SO4, and evaporated. The residue was purified by
column chromatography over silica gel (nꢀhexane/ethyl aceate=1:1) to give 22a as a paleꢀyellow solid
(88 mg, 85%). mp 80–82 °C; IR (neat) ν (cm−1) = 3310, 2944, 2839, 1676, 1517, 1446, 1248, 1024,
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758; H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 6.97 (dd, J = 8.3, 1.8 Hz, 1H), 6.85–6.81 (m, 2H),
6.78 (s, 1H), 6.68–6.64 (m, 2H), 6.61–6.58 (m, 2H), 4.79 (d, J = 6.8 Hz, 1H), 4.56 (d, J = 6.8 Hz, 1H),
4.25–4.12 (m, 2H), 3.89 (s, 3H), 3.86 (s, 3H), 3.80 (s, 3H), 3.71 (s, 3H), 3.64 (s, 3H), 3.52 (s, 3H),
3.27 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.3, 149.9, 148.8, 148.7,
148.2, 147.3, 143.5, 132.2, 127.6, 127.4, 124.5, 123.6, 122.5, 119.9, 119.2, 116.8, 115.3, 113.5, 111.2,
111.1, 110.7, 101.6, 96.5, 60.0, 56.2, 55.9, 55.8, 55.7, 55.6, 55.55, 55.52, 14.2; HRMS (ESI) m/z
calcd. for C33H38NO10[M+H]+: 608.2490, found: 608.2486.
1,2ꢀbis(3,4ꢀDimethoxyphenyl)ꢀ7,8ꢀdimethoxychromeno[3,4ꢀb]pyrrolꢀ4(3H)ꢀone (23a). Under nitrogen
atmosphere, a solution of 22a (270 mg, 0.21 mmol) and pꢀTsOH·H2O (8 mg, 10 mol %) in MeOH (10
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mL) was refluxed for 16 h. After cooling to room temperature, the mixture was quenched with
saturated aqueous NaHCO3 and extracted with DCM. The combined organic layer was washed with
brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography over
silica gel (nꢀhexane/ethyl acetate = 1:1) to give 23a as a paleꢀyellow solid (219 mg, 95%). mp 170–
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172 °C; IR (neat) ν (cm−1) = 3281, 2927, 2846, 1694, 1523, 1464, 1258, 1144, 1023, 859, 806; H
NMR (400 MHz, DMSOꢀd6) δ 12.75 (s, 1H), 7.21 (d, J = 1.9 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 7.07–
7.00 (m, 3H), 6.95–6.86 (m, 2H), 6.57 (s, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.73 (s, 3H), 3.70 (s, 3H),
3.63 (s, 3H), 3.33 (s, 3H); 13C NMR (100 MHz, DMSOꢀd6) δ 154.9, 149.8, 149.2, 149.1, 149.0, 148.7,
146.2, 145.6, 139.3, 128.2, 127.6, 123.8, 123.6, 120.9, 117.2, 115.0, 114.9, 112.9, 111.9, 110.2, 104.9,
101.5, 56.3, 56.2, 55.9, 55.6, 55.4; HRMS (ESI) m/z calcd. for C29H28NO8 [M+H]+: 518.1809, found:
518.1797.
3ꢀ(2,2ꢀDiethoxyethyl)ꢀ1,2ꢀbis(3,4ꢀdimethoxyphenyl)ꢀ7,8ꢀdimethoxychromeno[3,4b]pyrrol 4(3H)ꢀone
(24a). Under nitrogen atmosphere, a solution of 23a (102 mg, 0.197 mmol), 2ꢀbromoꢀ 1,1ꢀ
diethoxyethane (178 ꢁL, 1.18 mmol), and Cs2CO3 (385.69 mg, 1.18 mmol) in DMF (20 mL) was
stirred for 38 h at 110 °C. After cooling to room temperature, the mixture was diluted with water,
extracted with ethyl acetate. The combined organic layer dried over Na2SO4 and evaporated. The
residue was purified by column chromatography over silica gel (nꢀhexane/ethyl acetate = 2:1) to give
24a as a yellowish gummy solid (100 mg, 80%). IR (neat) ν (cm−1) = 2936, 2844, 1706, 1527, 1457,
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1260, 1143, 1037, 821, 759; H NMR (300 MHz, CDCl3) δ 6.99–6.88 (m, 4H), 6.87 – 6.76 (m, 4H),
5.02 (t, J = 5.6 Hz, 1H), 4.50 (brs, 2H), 3.91 (s, 3H), 3.88 (s, 6H), 3.73 (s, 3H), 3.72 (s, 3H), 3.71–
3.64 (m, 2H), 3.51 (s, 3H), 3.49–3.36 (m, 2H), 1.14 (t, J = 6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ
155.6, 149.1, 149.0, 148.7, 148.4, 148.2, 146.3, 145.5, 144.3, 127.7, 127.0, 124.1, 123.6, 122.3, 118.4,
114.6, 114.3, 111.0, 110.7, 110.2, 104.9, 102.6, 100.5, 64.1, 56.1, 55.9, 55.82, 55.76, 55.7, 48.8, 15.3.
HRMS (ESI) m/z calcd. for C35H39NNaO10 [M+Na]+: 656.2466, found: 656.2471.
Lamellarin D trimethyl ether (2)6d Under nitrogen atmosphere, 1 drop of TfOH was added to a
solution of 24a (40 mg, 63.1 ꢁmol) in DCM (4.0 mL) at 0 °C. After 24 h of stirring at 0 °C, Na2CO3
(5.0 mg) and Na2SO4 (5.0 mg) were added to the mixture. The suspension was allowed to warm to
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room temperature and then passed through a pad of celite. The filtrate was evaporated, and the residue
was purified by column chromatography over silica gel (nꢀhexane/ethyl acetate = 1:3) to give
lamellarin D trimethyl ether (2) as a colourless solid (32 mg, 94%). mp 277 – 278 °C; IR (neat) ν
(cm−1) = 3011, 2939, 2837, 1698, 1616, 1459, 1419, 1265, 1162, 1038, 940, 855, 753; 1H NMR (500
MHz, CDCl3) δ 9.20 (d, J = 7.3 Hz, 1H), 7.24 (dd, J = 8.1, 1.9 Hz, 1H), 7.18 (s, 1H), 7.17 (d, J = 2.6
Hz, 1H),7.16 (d, J = 6 Hz, 1H), 7.08 (s, 1H), 7.03 (d, J = 7.4 Hz, 1H), 6.89 (s, 1H), 6.74 (s, 1H), 4.00
(s, 3H), 3.98 (s, 3H), 3.90 (s, 3H), 3.86 (s, 3H), 3.49 (s, 3H), 3.47 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 155.4, 150.1, 149.9, 149.5, 149.2, 149.1, 146.7, 145.5, 134.3, 129.3, 128.2, 124.8, 124.1,
123.3, 119.1, 114.5, 112.3, 112.0, 110.9, 109.8, 107.8, 107.4, 105.3, 105.0, 100.5, 56.3, 56.2, 56.0,
55.9, 55.5, 55.2; HRMS (ESI) m/z calcd. for C31H28NO8 [M+H]+: 542.1809, found: 542.1815. The
spectral data are in accordance with the literature values (See the Supporting Information for detail
comparison of 1H and 13C NMR).
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Lamellarin H (3).6d To a stirred solution of 2 (15 mg, 0.027 mmol, 1.00 equiv) in dry DCM (5 mL)
under nitrogen, BBr3 (1.7 mL, 0.277 mmol, 1 M in DCM, 10 equiv) was added dropwise at −78 °C
and was stirred at same temperature for another 15 min followed by removal of the cooling bath. The
darkꢀred solution was stirred for an additional 20 h at room temperature and then quenched by
addition of MeOH (4 mL). The solvent was removed and the residue suspended in water (30 mL)
followed by extraction with ethyl acetate (3 × 20 mL). The combined organic layers were dried over
anhydrous Na2SO4, and the solvent was concentrated in vacuo. The residue was purified by column
chromatogarphy on silica gel to furnish lamellarin H (3) as a brownish amorphous solid (10 mg,
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83%). mp > 300 °C; IR (neat) ν (cm−1) = 3394, 2256, 2129, 1658, 1048, 1023, 994, 824, 761; H
NMR (500 MHz, DMSOꢀd6) δ 9.98 (br s, 1H), 9.75 (br s, 1H), 9.40 (br s, 1H), 9.19 (br s, 2H), 8.99
(d, J = 7.3 Hz, 1H), 8.90 (br s, 1H),7.14 (d, J = 8.4 Hz, 1H), 7.14 (s, 1H), 6.98 (d, J = 7.9 Hz, 1H),
6.95 (s, 1H), 6.80 (s, 1H), 6.79 (d, J = 1.8 Hz, 1H), 6.71 (dd, J = 7.8, 1.5 Hz, 1H), 6.56 (s, 1H).13C
NMR (125 MHz, DMSOꢀd6) δ 155.0, 148.1, 147.3, 147.0, 146.7, 146.0, 145.7, 142.6, 134.4, 129.3,
125.9, 124.2, 121.9, 121.6, 118.6, 118.0, 117.5, 113.0, 111.9, 111.7, 110.1, 110.0, 109.2, 106.8,
103.8; HRMS (ESI) m/z calcd. for C25H15NNaO8 [M+Na]+: 480.0690, found: 480.0684. The spectral
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data are in accordance with the literature values (See the Supporting Information for detail
comparison of 1H and 13C NMR).
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1,2ꢀBis(4ꢀisopropoxyꢀ3ꢀmethoxyphenyl)ethyne (20b). According to the described procedure for 20a,
the same procedure followed for 20b; In a round bottam flask under nitrogen atmosphere placed
propiolic acid (700 mg, 1.0 mol, 1 equiv), 4ꢀbromoꢀ1ꢀisopropoxyꢀ2ꢀmethoxybenzene (21b) (462 mg,
2.0 mol, 2 equiv), PdCl2(PPh3)2 (171mg, 5 mol%, 0.05 equiv), dppb (426 mg, 10 mol %, 0.1 equiv),
DBU (3.044 gm, 2.0 mol, 2 equiv) and DMSO (30 mL).The resulting reaction mixture was heated at
110⁰ C for 24 h, after completion of the reaction it was diluted with saturated NH4Cl solution (250
mL) and extracted with ethyl acetate (50 ml × 3), washed with brine, dried on Na2SO4. The solvent
was removed under vacuo, crude reaction mixture was purified by using column chromatography on
silica gel to furnish 20b as a white solid (1.7 gm, 50%); mp 163– 165 °C; IR (neat) ν (cm−1) = 2981,
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2928, 2356, 1669, 1523, 1460, 1335, 1233, 1140, 1105, 1037, 952, 855, 767; H NMR (400 MHz,
CDCl3) δ 7.08 (dd, J = 8.3, 1.8 Hz, 2H), 7.03 (d, J = 1.7 Hz, 2H), 6.85 (s, 1H), 6.83 (s, 1H), 4.62–4.51
(m, 2H), 3.87 (s, 6H), 1.38 (d, J = 6.1 Hz, 12H); 13C NMR (100 MHz, CDCl3) δ 149.9, 147.6, 124.5,
115.8, 115.0, 114.9, 88.0, 71.3, 55.9, 22.0; HRMS (ESI) m/z calcd. for C22H27O4 [M+H]+: 355.1909,
found: 355.1909.
Ethyl 4,5ꢀbis(4ꢀisopropoxyꢀ3ꢀmethoxyphenyl)ꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate (17b). According to the
procedure described for the preparation of 17a, the same procedure followed for 17b using ethyl 2ꢀ
acetamidoacrylate 16a (400 mg, 2.54 mmol), 1,2ꢀbis(4ꢀisopropoxyꢀ3ꢀmethoxyphenyl)ethyne 20b (951
mg, 2.79 mmol), [RuCl2(pꢀcymene)]2 (78 mg, 5.0 mol %) and Cu(OAc)2•H2O (508 mg, 2.54 mmol) in
PEGꢀ400 (5 mL) to furnish 17b as a gummy solid (960 mg, 87%); IR (neat) ν (cm−1) = 3302, 2977,
2933, 1680, 1516, 1472, 1239, 1114, 1031, 951, 855, 816, 766; 1H NMR (300 MHz, CDCl3) δ 9.26 (s,
1H), 7.03 (d, J = 2.6 Hz, 1H), 6.96 (dd, J = 8.2, 2.0 Hz, 1H), 6.89–6.82 (m, 5H), 4.58–4.45 (m, 2H),
4.32 (q, J = 7.1 Hz, 2H), 3.69 (s, 3H), 3.65 (s, 3H), 1.40 – 1.34 (m, 15H); 13C NMR (75 MHz, CDCl3)
δ 161.3, 150.1, 147.2, 145.8, 133.0, 128.8, 124.9, 123.4, 121.7, 120.7, 120.1, 116.4, 116.0, 115.5,
112.6, 112.0, 71.5, 71.39, 60.4, 55.8, 22.1, 22.0, 14.5; HRMS (ESI) m/z calcd. for C27H33NNaO6
[M+Na]+: 490.2206, found: 490.2187.
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Ethyl 3ꢀbromoꢀ4,5ꢀbis(4ꢀisopropoxyꢀ3ꢀmethoxyphenyl)ꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate (19b). According to
the procedure described for the preparation of 19a, the same procedure followed for 19b; using 17b
(460 mg, 0.985 mmol), NBS (175 mg, 0.985 mmol) DMF (10 mL) to give 19b as light yellow solid
(460 mg, 85%). mp 128–130 °C; IR (neat) ν (cm−1) = 3284, 2977, 2933, 1670, 1554, 1517, 1472,
1382, 1243, 1037, 1139, 1108, 1037, 951, 860, 763; 1H NMR (400 MHz, CDCl3) δ 9.42 (s, 1H), 6.90–
6.85 (m, 2H), 6.84–6.77 (m, 3H), 6.69 (d, J = 2.0 Hz, 1H), 4.59–4.46 (m, 2H), 4.37 (q, J = 7.1 Hz,
2H), 3.74 (s, 3H), 3.55 (s, 3H), 1.42–1.34 (m, 15H); 13C NMR (100 MHz, CDCl3) δ 160.5, 149.9,
147.3, 146.5, 133.3, 126.4, 124.4, 123.7, 123.1, 119.3, 119.2, 115.3, 115.1, 114.7, 111.5, 105.9, 71.2,
60.8, 55.9, 55.6, 22.1, 22.0, 14.4; HRMS (ESI) m/z calcd. for C27H32BrNNaO6 [M+Na]+: 568.1305,
found: 568.1322.
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Ethyl 4,5ꢀbis(4ꢀisopropoxyꢀ3ꢀmethoxyphenyl)ꢀ3ꢀ(4ꢀisopropoxyꢀ5ꢀmethoxyꢀ2 (methoxymethoxy)phenyl)
ꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate (22b). According to the procedure described for the preparation of 22a, the
same procedure followed for 22b; using 19b (120 mg, 0.219 mmol), 18b (89 mg, 0.318 mmol),
Pd(dba)2 (13 mg, 10 mol %), dppf (13 mg, 10 mol %), Na2CO3 (163 mg, 1.53 mmol), DME (5.0 mL),
and degassed water (1.0 mL) to furnish 22b as a white solid (130 mg, 85%); mp 98–100 °C; IR (neat)
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ν (cm−1) = 3296, 2976, 2932, 1667, 1510, 1464, 1381, 1312, 1245, 1146, 1112, 1029, 862, 760; H
NMR (400 MHz, CDCl3) δ 9.17 (s, 1H), 6.97 – 6.93 (m, 1H), 6.87–6.78 (m, 3H), 6.69 – 6.63 (m, 2H),
6.59–6.54 (m, 2H), 4.79 (d, J = 6.8 Hz, 1H), 4.57–4.38 (m, 4H), 4.24–4.11 (m, 2H), 3.65 (s, 3H), 3.58
(s, 3H), 3.47 (s, 3H), 3.24 (s, 3H), 1.40–1.33 (m, 12H), 1.30 (d, J = 6.1 Hz, 6H), 1.13 (t, J = 7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 161.4, 149.9, 149.8, 149.7, 146.97, 146.95,145.3, 145.1, 132.2,
128.0, 127.6, 124.8, 123.6, 122.5, 119.6, 119.2, 117.6, 116.1, 115.6, 115.2, 114.2, 111.9, 105.9, 96.4,
71.6, 71.3, 60.0, 56.4, 55.6, 55.5, 55.4, 22.04, 22.00, 14.2; HRMS (ESI) m/z calcd. for C39H49NNaO10
[M+Na]+: 714.3249, found: 714.3231.
7ꢀIsopropoxyꢀ1,2ꢀbis(4ꢀisopropoxyꢀ3ꢀmethoxyphenyl)ꢀ8ꢀmethoxychromeno[3,4ꢀb]pyrrolꢀ4(3H)ꢀone
(23b). According to the procedure described for the preparation of 23a, the same procedure followed
for 23b; using 22b (130 mg, 0.205 mmol) and pꢀTsOH·H2O (4 mg, 10 mol%) in MeOH (10 mL) to
furnish 23b as a white solid (132 mg, 92%); mp 145– 147 °C; IR (neat) ν (cm−1) = 3283, 2976, 2935,
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1691, 1521, 1464, 1440, 1383, 1262, 1281, 1146, 1110, 1033, 1009, 940, 858, 829, 761; H NMR
(400 MHz, CDCl3) δ10.02 (s, 1H), 7.05 – 6.93 (m, 6H), 6.86 – 6.78 (m, 2H), 4.62 – 4.51 (m, 3H),
3.78 (s, 3H), 3.65 (s, 3H), 3.47 (s, 3H), 1.40 (d, J = 6.1 Hz, 12H), 1.37 (d, J = 6.1 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ 156.1, 150.9, 150.0, 147.6, 147.3, 146.8, 146.7, 146.2, 138.9, 129.0, 127.8,
123.5, 123.4, 119.7, 117.2, 116.5, 115.0, 114.9, 114.7, 111.2, 110.5, 105.0, 103.8, 71.7, 71.5, 71.2,
56.1, 55.6, 55.5, 22.0, 21.8; HRMS (ESI) m/z calcd. forC35H40NO8 [M+H]+: 602.2676, found:
602.2673.
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3ꢀ(2,2ꢀDiethoxyethyl)ꢀ7ꢀisopropoxyꢀ1,2ꢀbis(4ꢀisopropoxyꢀ3ꢀmethoxyphenyl)ꢀ8ꢀmethoxychromeno[3,4ꢀ
b]pyrrolꢀ4(3H)ꢀone (24b). According to the procedure described for the preparation of 24a, the same
procedure followed for 24b; using 23b (100 mg, 0.144 mmol), 2ꢀbromoꢀ 1,1ꢀdiethoxyethane (130 ꢁL,
0.868 mmol), and Cs2CO3 (283 mg, 0.868 mmol) in DMF (10 mL) to furnish 24b as gummy solid (70
mg, 67%); IR (neat) ν (cm−1) = 3776, 3712, 3590, 2920, 2354, 1676, 1592, 1482, 1435, 1291, 1221,
1031, 924, 770; 1H NMR (400 MHz, CDCl3) δ 7.01 – 6.91 (m, 3H), 6.90 – 6.79 (m, 4H), 6.72 (d, J =
1.7 Hz, 1H), 5.00 (t, J = 5.6 Hz, 1H), 4.60 – 4.47 (m, 5H), 3.76 – 3.67 (m, 2H), 3.66 (s, 3H), 3.65 (s,
3H), 3.47 (s, 3H), 3.47 – 3.36 (m, 2H), 1.40 (d, J = 6.1 Hz, 6H), 1.38 – 1.33 (m, 12H), 1.16 – 1.08 (m,
6H); 13C NMR (100 MHz, CDCl3) δ 155.7, 150.2, 149.5, 147.4, 147.2, 146.5, 146.3, 146.2, 144.4,
127.8, 127.6, 123.9, 123.5, 122.4, 118.5, 115.9, 115.2, 115.0, 114.6, 114.5, 110.3, 105.3, 103.5, 102.6,
71.5, 71.1, 64.1, 55.8, 55.6, 48.8, 22.0, 21.8, 15.4; HRMS (ESI) m/z calcd. for C41H51NNaO10
[M+Na]+: 740.3405, found: 740.3420.
3,11ꢀDiisopropoxyꢀ14ꢀ(4ꢀisopropoxyꢀ3ꢀmethoxyphenyl)ꢀ2,12ꢀdimethoxyꢀ6Hꢀchromeno[4',3':4,5]
pyrrolo[2,1ꢀa]isoquinolinꢀ6ꢀone (25).11 According to the procedure described for the preparation of 2,
the same procedure followed for 25; using 24b (35 mg, 48.8 ꢁmol) and TfOH to furnish 25 as a white
solid (28.3 mg, 94%); mp 189–190 °C; IR (neat) ν (cm−1) = 3777, 3502, 2979, 2933, 2355, 1707,
1601, 1475, 1429, 1384, 1268, 1172, 1113, 1035, 944, 860, 766; 1H NMR (400 MHz, CDCl3) δ 9.23
(d, J = 7.3 Hz, 1H), 7.19 (s, 1H), 7.17 (d, J = 1.0 Hz, 2H), 7.15 – 7.12 (m, 1H), 7.10 (s, 1H), 7.02 (d, J
= 7.4 Hz, 1H), 6.97 (s, 1H), 6.76 (s, 1H), 4.73 – 4.53 (m, 3H), 3.84 (s, 3H), 3.45 (s, 3H), 3.44 (s, 3H),
1.43 (d, J = 6.1 Hz, 12H), 1.40 (d, J = 6.1 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 155.6, 151.4,
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150.2, 148.5, 147.9, 147.2, 146.6, 146.5, 134.4, 129.4, 128.8, 124.7, 123.9, 123.2, 119.0, 116.9, 115.0,
112.3, 111.0, 110.5, 110.0, 107.8, 105.7, 105.5, 103.5, 71.8, 71.5, 71.2, 56.2, 55.4, 55.1, 21.9, 21.8;
HRMS (ESI) m/z calcd. for C37H40NO8 [M+H]+: 626.2754, found: 626.2750.
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Lamellarin D (1).11 Following the procedure by Iwao et al.6a; under an argon atmosphere, a DCM
solution of BCl3 (1.0 M, 200 ꢁL, 0.192 mmol) was added dropwise to a solution of 25 (15 mg, 24.1
ꢁmol) in DCM (5.0 mL) at −78 °C, and the mixture was allowed to warm to room temperature. After
4h of stirring at room temperature, the mixture was quenched with saturated aqueous NaHCO3, and
the crude reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine,
dried over Na2SO4, and evaporated. The residue was purified by column chromatography over silica
gel (ethyl acetate) to give lamellarin D (1) as a white solid (9.5 mg, 79%); mp > 300 °C; IR (neat) ν
(cm−1) = 3409, 2254, 2128, 1658, 997, 824, 762; 1H NMR (400 MHz, DMSO –d6) δ 9.93 (s, 1H), 9.82
(s, 1H), 9.33 (s, 1H), 9.01 (d, J = 7.4 Hz, 1H), 7.24 – 7.15 (m, 3H), 7.14 (s, 1H), 7.10 (d, J = 8.0 Hz,
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1H), 7.02 (d, J = 7.9 Hz, 1H), 6.87 (s, 1H), 6.72 (s, 1H), 3.77 (s, 3H), 3.38 (s, 3H), 3.38 (s, 3H); C
NMR (100 MHz, DMSO –d6) δ 154.8, 149.2, 149.0, 148.8, 148.3, 147.3, 146.8, 145.0, 134.6, 129.5,
125.9, 125.2, 124.3, 122.5, 118.0, 116.9, 115.4, 112.9, 112.0, 111.3, 108.8, 106.9, 106.2, 105.8, 104.2,
56.4, 55.5, 55.0; HRMS (ESI) m/z calcd. for C28H22NO8 [M+H]+: 500.1345, found: 500.1346. The
spectral data are in accordance with the literature values (See the Supporting Information for detail
comparison of 1H and 13C NMR).
Ethyl 4,5ꢀbis(4ꢀ(trifluoromethyl)phenyl)ꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate (17c).20 According to the
procedure described for the preparation of 17a, the same procedure followed for 17c; using ethyl 2ꢀ
acedamidoacrylate 16a (220 mg, 1.39 mmol), 1,2ꢀbis(4ꢀ(trifluoromethyl)phenyl)ethyne 20c (527 mg,
1.67 mmol), [RuCl2(pꢀcymene)]2 (42.85 mg, 5.0 mol %) and Cu(OAc)2·H2O (280 mg, 1.39 mmol) in
PEGꢀ400 (5 mL) to yield 17c as a white solid (400 mg, 84%); mp 206–208 °C; IR (neat) ν (cm−1 ) =
3296, 3025, 2354, 1690, 1462, 1223, 1011, 834, 755, 671; 1H NMR (400 MHz, CDCl3) δ 9.81 (s, 1H),
7.62 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H),
7.08 (d, J = 2.6 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 161.3, 138.7, 135.0, 132.1, 130.2 (d, JCꢀF = 44 Hz), 128.6, 128.4, 125.8 (d, JCꢀF = 5 Hz),
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125.8 (d, JCꢀF = 5 Hz),123.7 (d, JCꢀF = 7 Hz),122.3 (d, JCꢀF = 32 Hz), 116.7, 60.9, 14.3; HRMS (ESI)
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Ethyl 3ꢀbromoꢀ4,5ꢀbis(4ꢀ(trifluoromethyl)phenyl)ꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate (19c). According to the
procedure described for the preparation of 19a, the same procedure followed for 19c; using 17c (300
mg, 0.702 mmol) and NBS (138 mg, 0.775 mmol) DMF (8 mL) to give 19c as a white solid (250 mg,
70%); mp 190–192 °C; IR (neat) ν (cm−1) = 3261, 2987, 1667, 1472, 1323, 1265, 1169, 1122, 1064,
1017, 846, 765; 1H NMR (500 MHz, CDCl3) δ 9.98 (s, 1H), 7.63 (d, J = 7.9 Hz, 2H), 7.56 (d, J = 8.0
Hz, 2H), 7.39 (d, J = 7.8 Hz, 2H), 7.35 (d, J = 7.9 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.0
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 160.6, 136.7, 134.0, 132.2, 131.0, 130.3 (q, JCꢀF = 32.5 Hz),
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129.7 (q, JCꢀF = 32.5 Hz), 128.0, 125.8 (d, JCꢀF = 2.5 Hz), 125.4 (d, JCꢀF = 3.5 Hz), 125.0(d, JCꢀF
=
43.75 Hz),124.6, 122.9 (d, JCꢀF= 43.75 Hz), 121.3, 105.6, 61.4, 14.3; HRMS (ESI) m/z calcd. for
C21H15BrF6NO2 [M+H]+: 506.0190, found: 506.0188.
Ethyl 3ꢀ(4,5ꢀdimethoxyꢀ2ꢀ(methoxymethoxy)phenyl)ꢀ4,5ꢀbis(4ꢀ(trifluoromethyl)phenyl)ꢀ1Hꢀpyrroleꢀ2ꢀ
carboxylate (22c). According to the procedure described for the preparation of 22a, the same
procedure followed for 22c; using 19c (190 mg, 0.375 mmol), 12a (136 mg, 0.561 mmol), Pd(dba)2
(21 mg, 10 mol %), dppf (20 mg, 10 mol %), Na2CO3 (278 mg, 2.62 mmol), DME (5.0 mL), and
degassed water (1.0 mL) to give 22c as a white solid (210 mg, 90%); mp 188–190 °C; IR (neat) ν
(cm−1) = 3282, 2942, 1670, 1617, 1444, 1323, 1214, 1163, 1122, 1066, 1016, 848, 758; 1H NMR (300
MHz, CDCl3) δ 9.75 (s, 1H), 7.57 (d, J = 8.3 Hz, 2H), 7.45 – 7.37 (m, 4H), 7.12 (d, J = 8.0 Hz, 2H),
6.77 (s, 1H), 6.61 (s, 1H), 4.80 (d, J = 6.9 Hz, 1H), 4.57 (d, J = 6.9 Hz, 1H), 4.22 – 4.05 (m, 2H), 3.87
(s, 3H), 3.69 (s, 3H), 3.19 (s, 3H), 1.12 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 161.3,
149.7, 149.3, 143.5, 138.3, 134.9, 131.2, 130.2,129.8 (q, JCꢀF = 32.5 Hz), 128.5 (q, JCꢀF = 32.5 Hz),
128.1, 127.7, 125.7 (d, JCꢀF = 3.75 Hz), 125.0 (d, JCꢀF = 3.75 Hz), 124.1, 122.2 (d, JCꢀF = 21 Hz), 121.0,
115.3, 115.2, 101.1, 96.1, 60.5, 56.3, 55.9, 55.5, 14.1; HRMS (ESI) m/z calcd. for C31H28F6NO6
[M+H]+: 624.1815, found: 624.1809.
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7,8ꢀDimethoxyꢀ1,2ꢀbis(4ꢀ(trifluoromethyl)phenyl)chromeno[3,4ꢀb]pyrrolꢀ4(3H)ꢀone (23c). According
to the procedure described for the preparation of 23a, the same procedure followed for 23c; using 22c
(170 mg, 0.272 mmol) and pꢀTsOH·H2O (4.7 mg, 10 mol %) in MeOH (10 mL) to yield 23c as white
solid (134 mg, 92%); mp 311– 313 °C; IR (neat) ν (cm−1) = 3275, 2926, 2356, 1693, 1329, 1133,
1072, 1022, 847, 771; 1H NMR (500 MHz, DMSOꢀd6) δ 13.30 (s, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.74
(d, J = 8.3 Hz, 2H), 7.69 (d, J = 7.9 Hz, 2H), 7.62 (d, J = 8.2 Hz, 2H), 7.10 (m,1H), 6.36 (m, 1H), 3.81
(s, 3H), 3.30 (s, 3H); 13C NMR (125 MHz, DMSOꢀd6) δ 154.8, 149.4, 146.2, 145.7, 139.2, 137.7,
134.6, 132.7, 129.6, 129.1 (q, JCꢀF = 43.5 Hz), 128.7 (q, JCꢀF = 43.5 Hz), 127.5, 126.4 (d, JCꢀF = 1.25
Hz), 125.9 (d, JCꢀF = 2.5 Hz), 125.6, 123.5 (d, JCꢀF = 25 Hz), 117.5, 116.7, 109.4, 104.2, 101.7, 56.4,
55.0; HRMS (ESI) m/z calcd. for C27H17F6NNaO4 [M+Na]+: 556.0954, found: 556.0965.
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Methyl 4,5ꢀbis(4ꢀfluorophenyl)ꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate (17d). According to the procedure
described for the preparation of 17a, the same procedure followed for 17d; using methyl 2ꢀ
acetamidoacrylate 16b (180 mg, 1.25 mmol), 1,2ꢀbis(4ꢀfluorophenyl)ethyne 20c (270 mg, 1.26
mmol), [RuCl2(pꢀcymene)]2 (38 mg, 5.0 mol %) and Cu(OAc)2•H2O (251 mg, 1.25 mmol) in PEGꢀ
400 (4 mL) to obtain 17d as white solid (260 mg, 76%); mp 164–166 °C; IR (neat) ν (cm−1) = 3299,
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2362, 1689, 1521, 1456, 1287, 1228, 1160, 1010, 837, 769; H NMR (400 MHz, CDCl3) δ9.51 (s,
1H), 7.38 – 7.30 (m, 2H), 7.25 – 7.18 (m, 2H), 7.11 – 6.87 (m, 5H), 3.84 (s, 3H); 13C NMR (100
MHz, CDCl3 δ 162.5 (d, JCꢀF = 247 Hz), 161.70, 161.69 (d, JCꢀF = 244 Hz), 132.4, 131.2 (d, JCꢀF = 3
Hz), 130.0 (d, JCꢀF = 8 Hz), 129.8 (d, JCꢀF = 8 Hz),127.9 (d, JCꢀF = 3 Hz), 123.1, 122.1, 116.7, 115.7 (d,
JCꢀF = 22 Hz), 115.4 (d, JCꢀF = 21 Hz), 51.7; HRMS (ESI) m/z calcd. for C18H14F2NO2[M+H]+:
314.0987, found: 314.0983.
Methyl 3ꢀbromoꢀ4,5ꢀbis(4ꢀfluorophenyl)ꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate (19d). According to the procedure
described for the preparation of 19a, the same procedure followed for 19d; using 17d (250 mg, 0.798
mmol) and NBS (157 mg, 0.882 mmol) DMF (8 mL) to give 19d as a white solid solid (240 mg,
76%); mp 190–192 °C; IR (neat) ν (cm−1) = 3299, 2956, 2361, 1674, 1522, 1464, 1220, 1160, 1043,
839, 767; 1H NMR (400 MHz, CDCl3) δ 9.72 (s, 1H), 7.25 – 7.13 (m, 4H), 7.10 – 6.90 (m, 4H), 3.88
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.5 (d, JCꢀF = 248 Hz), 162.2 (d, JCꢀF = 245 Hz), 132.7,
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132.3 (d, JCꢀF = 8 Hz), 129.5 (d, JCꢀF = 8 Hz), 129.0 (d, JCꢀF = 3 Hz), 126.8 (d, JCꢀF = 3 Hz), 124.0,
119.9, 115.8 (d, JCꢀF = 22 Hz), 115.4 (d, JCꢀF = 21 Hz), 105.9, 51.9; HRMS (ESI) m/z calcd. for
C18H12BrF2NO2Na [M+Na]+: 413.9912, found: 413.9916.
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Methyl 3ꢀ(4,5ꢀdimethoxyꢀ2ꢀ(methoxymethoxy)phenyl)ꢀ4,5ꢀbis(4ꢀfluorophenyl)ꢀ1Hꢀpyrroleꢀ2ꢀcarboxy
late (22d). According to the procedure described for the preparation of 22a, the same procedure
followed for 22d; using 13d (196 mg, 0.500 mmol), 18a (182 mg, 0.752 mmol), Pd(dba)2 (29 mg, 10
mol %), dppf (28 mg, 10 mol %), Na2CO3 (371 mg, 3.5 mmol), DME (5.0 mL), and degassed water to
furnish 22d as a white solid (185 mg, 72%); mp 109–111°C; IR (neat) ν (cm−1) = 3298, 2948, 2359,
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1680, 1513, 1451, 1218, 1157, 1010, 841, 759; H NMR (400 MHz, CDCl3) δ 9.50 (s, 1H), 7.29 –
7.25 (m, 2H), 7.03 – 6.89 (m, 4H), 6.88 – 6.76 (m, 3H), 6.59 (s, 1H), 4.79 (d, J = 6.8 Hz, 1H), 4.57 (d,
J = 6.9 Hz, 1H), 3.87 (s, 3H), 3.70 (s, 3H), 3.68 (s, 3H), 3.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
162.3 (d, JCꢀF = 247 Hz), 161.7, 161.5 (d, JCꢀF = 244 Hz), 149.8, 148.9, 143.4, 131.7, 131.6 (d, JCꢀF = 8
Hz), 130.5 (d, JCꢀF = 3 Hz), 129.6 (d, JCꢀF = 8 Hz), 127.7 (d, JCꢀF = 3 Hz), 127.6, 123.5, 119.4, 115.7
(d, JCꢀF = 21 Hz), 115.2, 115.0 (d, JCꢀF = 21Hz), 101.3, 96.4, 56.2, 55.8, 55.6, 51.4; HRMS (ESI)
calcd. for C28H25F2NNaO6 [M+Na]+: 532.1542, found: 532.155.
1,2ꢀBis(4ꢀfluorophenyl)ꢀ7,8ꢀdimethoxychromeno[3,4ꢀb]pyrrolꢀ4(3H)ꢀone (23d). According to the
procedure described for the preparation of 23a, the same procedure followed for 23d; using 22d (110
mg, 0.216 mmol) and pꢀTsOH·H2O (4 mg, 10 mol%) in MeOH (10 mL) to yield 23d as gummy solid
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(85 mg, 91%); IR (neat) ν (cm−1) = 3200, 2842, 1687, 1513, 1284, 1218, 1080, 1020, 840, 760; H
NMR (400 MHz, DMSOꢀd6) δ 12.98 (s, 1H), 7.49 – 7.40 (m, 4H), 7.38 – 7.30 (m, 2H), 7.23 – 7.15
(m, 2H), 7.07 (s, 1H), 6.52 (s, 1H), 3.80 (s, 3H), 3.35 (s, 3H); 13C NMR (100 MHz, DMSOꢀd6) δ
162.4 (d, JCꢀF = 245 Hz), 162.3 (d, JCꢀF = 243 Hz), 154.8, 149.2, 146.2, 145.7, 138.7, 133.7 (d, JCꢀF = 8
Hz), 131.0 (d, JCꢀF = 8 Hz), 127.6, 127.4 (d, JCꢀF = 3 Hz), 116.8, 116.4 (d, JCꢀF = 21 Hz), 115.9 (d, JCꢀF
= 21 Hz), 115.7, 109.9, 104.5, 101.6, 56.3, 55.4; HRMS (ESI) calcd. for C25H17F2NNaO4 [M+Na]+:
456.1018, found: 456.102.
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Ethyl 4,5ꢀbis(4ꢀmethoxyphenyl)ꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate (17e). According to the procedure
described for the preparation of 17a, the same procedure followed for 17e; using ethyl 2ꢀ
acetamidoacrylate 16a (300 mg, 1.90 mmol), 1,2ꢀbis(4ꢀmethoxyphenyl)ethyne 20e (500 mg, 2.10
mmol), [RuCl2(pꢀcymene)]2 (58 mg, 5.0 mol %) and Cu(OAc)2•H2O (381 mg, 1.90 mmol) in PEGꢀ
400 (4 mL) to give 17e as a white solid (550 mg, 82%); mp 162–163 °C; IR (neat) ν (cm−1) = 3295,
2990, 2837, 1679, 1612, 1522, 1464, 1239, 1184, 1131, 1028, 833, 762; 1H NMR (400 MHz, CDCl3)δ
9.40 (s, 1H), 7.33 – 7.27 (m, 2H), 7.24 – 7.19 (m, 2H), 7.03 – 6.97 (m, 1H), 6.87 – 6.79 (m, 4H), 4.29
(q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 3.79 (s, 3H), 1.34 (t, J = 7.1 Hz,3H); 13C NMR (100 MHz, CDCl3) δ
161.4, 159.3, 158.1, 132.9, 129.5, 129.2, 128.0, 124.6, 123.1, 121.8, 116.5, 114.1, 113.8, 60.4, 55.21,
55.16, 14.5; HRMS (ESI) calcd. for C21H21NNaO4 [M+Na]+: 374.1363, found: 374.1371.
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Ethyl 3ꢀbromoꢀ4,5ꢀbis(4ꢀmethoxyphenyl)ꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate (19e). According to the procedure
described for the preparation of 19a, the same procedure followed for 19e; using 17e (140 mg, 0.398
mmol) and NBS (78 mg, 0.438 mmol) in DMF (6 mL) to give 19e as a brown solid (100 mg, 81%);
mp 172– 174 °C; IR (neat) ν (cm−1) = 3284, 2991, 2353, 1672, 1614, 1566, 1524, 1467, 1411, 1254,
1186, 1100, 1036, 835, 763; 1H NMR (400 MHz, CDCl3) δ 9.47 (s, 1H), 7.21 – 7.13 (m, 4H), 6.93 –
6.85 (m, 2H), 6.83 – 6.76 (m, 2H), 4.35 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 3.77 (s, 3H), 1.38 (t, J = 7.1
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 160.5, 159.4, 158.7, 133.2, 131.8, 128.8, 125.7, 124.0, 123.5,
119.3, 114.1, 113.7, 106.1, 60.8, 55.2, 55.1, 14.4; HRMS (ESI) m/z calcd. for C21H20BrNNaO4
[M+Na]+: 452.0468, found: 452.0469.
Ethyl
3ꢀ(4,5ꢀdimethoxyꢀ2ꢀ(methoxymethoxy)phenyl)ꢀ4,5ꢀbis(4ꢀmethoxyphenyl)ꢀ1Hꢀpyrroleꢀ2ꢀcarbo
xylate (22e). According to the procedure described for the preparation of 22a, the same procedure
followed for 22e; using 19e (100 mg, 0.232 mmol), 18a (85 mg, 0.351 mmol), Pd(dba)2 (14 mg, 10
mol %), dppf (13 mg, 10 mol %), Na2CO3 (171.5 mg, 1.62 mmol), DME (5.0 mL), and degassed
water (1.0 mL) to furnish 22e isolated as a brown solid (76 mg, 66%); mp 162–164°C; IR (neat) ν
(cm−1) = 3296, 2945, 2839, 2348, 1672, 1612, 1517, 1443, 1287, 1249, 1179, 1081, 1025, 838, 763;
1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 7.26–7.21 (m, 2H), 6.94–6.89 (m, 2H), 6.85–6.80 (m,
2H), 6.78 (s, 1H), 6.70–6.65 (m, 2H), 6.63 (s, 1H), 4.78 (d, J = 6.9 Hz, 1H), 4.53 (d, J = 6.9 Hz, 1H),
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4.27–4.09 (m, 2H), 3.86 (s, 3H), 3.80 (s, 3H), 3.74 (s, 3H), 3.69 (s, 3H), 3.28 (s, 3H), 1.16 (t, J = 7.1
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.3, 159.1, 157.9, 149.8, 148.6, 143.4, 132.2, 131.2, 128.9,
127.6, 127.2, 124.4, 123.5, 119.1, 116.7, 115.3, 114.0, 113.4, 101.5, 96.6, 60.0, 56.1, 55.8, 55.6, 55.2,
55.0, 14.3; HRMS (ESI) m/z calcd. for C31H34NO8 [M+H]+: 548.2279, found: 548.2267.
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7,8ꢀDimethoxyꢀ1,2ꢀbis(4ꢀmethoxyphenyl)chromeno[3,4ꢀb]pyrrolꢀ4(3H)ꢀone (23e). According to the
procedure described for the preparation of 23a, the same procedure followed for 23e; using 16e (40
mg, 0.0731 mmol) and pꢀTsOH·H2O (2 mg, 10 mol%) in MeOH (10 mL) to furnish 23e as white solid
(25 mg, 84%); mp 242–244 °C; IR (neat) ν (cm−1) = 3254, 2929, 1692, 1611, 1523, 1453, 1251, 1138,
1149, 1026, 839, 757; 1H NMR (400 MHz, DMSOꢀd6) δ 12.73 (s, 1H), 7.39 (d, J = 8.7 Hz, 2H), 7.29
(d, J = 7.7 Hz, 2H), 7.10–7.00 (m, 3H), 6.88 (d, J = 8.7 Hz, 2H), 6.54 (s, 1H), 3.80 (s, 3H), 3.79 (s,
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3H), 3.74 (s, 3H), 3.33 (s, 3H); C NMR (100 MHz, DMSOꢀd6) δ 159.6, 159.3, 154.8, 149.1, 146.2,
145.6, 139.5, 132.7, 130.0, 128.0, 127.0, 123.6, 116.9, 115.1, 114.9, 114.3, 110.2, 104.7, 101.5, 56.3,
55.7, 55.6, 55.4; HRMS (ESI) m/z calcd. for C27H23NNaO6 [M+Na]+: 480.1418, found: 480.1398.
ASSOCIATED CONTENT
Supporting Information
13
characterization of new compounds (1H, C NMR spectra). This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: srivaric@iict.res.in
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
D.M.L thanks Council of Scientific and Industrial Research (CSIR), New Delhi for senior research
fellowship. A.B.P thanks DST, New Delhi for the INSPIRE Faculty Award (CHꢀ157, GAP 0520). The
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authors thank CSIRꢀNew Delhi for financial support as part of XII fiveꢀyear programme project under
ORIGIN (CSCꢀ108). S.C thank DST for J. C. Bose fellowship (SB/S2/JCBꢀ002/2015).
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